Major depressive disorder (MDD) is characterized by a significant impairment in mood and motivation. It exhibits a chronic, relapsing course and is associated with high morbidity and mortality worldwide. Currently available antidepressants are inadequate for many patients, suggesting the potential existence of other biological substrate(s) that could be a therapeutic target in the treatment of depressive illness. Neurochemical basis in multiple signaling pathways has been considered to be associated with the pathophysiology of MDD. The G-protein coupled receptor (GPCR) mediated signaling is believed to be the most widely used mechanism in cells for various physiological and behavioral processes. The CB1 receptor, a GPCR, has recently been shown to play a critical role in neural circuitries mediating mood, motivation, and emotional behavior. Depressive disorder is a complex and multifactorial trait with important genetic and environmental contributing factors. Several genetic animal models have recently been developed and are critical in identifying factors underlying predisposition to depression. Extensive behavioral and biochemical studies have established the Wistar Kyoto (WKY) rat as a genetic animal model of depression. The mood altering ability of cannabinoids, and reported changes in the CB1 receptor density in the postmortem brain of depressed suicide victims led us to explore the role of the endocannabinoid system in the neurobiology of depression. We propose here to investigate the status of the central endocannabinoid system and to further examine whether the endocannabinoid-based drugs exhibit antidepressant properties in WKY rat. This study will further our understanding the mechanism underlying the genetic predisposition to depressive illness and may potentially aid in developing a novel therapeutic target for the treatment of depressive disorder. PUBLIC HEALTH RELEVANCE: Given the significance of acute and chronic burden associated with depressive disorder, understanding of its pathophysiological basis and development of an effective drug treatment is of paramount importance. The long-term goal of this study is to understand the cellular and molecular mechanisms of depressive behavior and to examine possible utility of the endocannabinoid system as potential therapeutic target for the treatment of depressive disorder.